CA1177823A - Cephalosporin derivatives - Google Patents
Cephalosporin derivativesInfo
- Publication number
- CA1177823A CA1177823A CA000373267A CA373267A CA1177823A CA 1177823 A CA1177823 A CA 1177823A CA 000373267 A CA000373267 A CA 000373267A CA 373267 A CA373267 A CA 373267A CA 1177823 A CA1177823 A CA 1177823A
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- Canada
- Prior art keywords
- compound
- formula
- oxo
- methyl
- salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
- C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
- C07D253/06—1,2,4-Triazines
- C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
- C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D253/075—Two hetero atoms, in positions 3 and 5
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Abstract
ABSTRACT
A cephalosporin derivative of the formula as well as readily hydrolysable esters and salts of this compound and hydrates of the compound of formula I or of esters and salts thereof.
Further, also corresponding preparations, the use of these products in the treatment of illnesses, the manufacture of the active substances as well as intermediates thereby occurring.
A cephalosporin derivative of the formula as well as readily hydrolysable esters and salts of this compound and hydrates of the compound of formula I or of esters and salts thereof.
Further, also corresponding preparations, the use of these products in the treatment of illnesses, the manufacture of the active substances as well as intermediates thereby occurring.
Description
~'7~3J ~3 The present invention is concerned wi-th novel cephalo-sporin derivatives, namely a cephalosporin derivative of the formula H H
- ~ H3C
CH20N = C - CONH ~ S ~ N ~ I
1 N ~ ~ N ~ CH2 - S ~ N
as well as readily hydrolysable esters and salts of this compound and hydrates of the compound of formula I or of esters and salts thereof, when prepared by the process described hereinafter, wherein the esters and salts are pharmaceutically acceptable.
As readily hydrolysable esters of the compound of formula I there are to be understood the compound of formula I in which the carboxy group is present in the form of a readily hydrolysable ester group. Examples of such esters, which can be of the conventional type, are the lower alkanoyloxyalkyl ester (e.g. the acetoxymethyl, pivaloyloxymethyl, l-acetoxyethyl and l-pivaloyloxyethyl ester), the lower alkoxycarbonyloxyalkyl esters (e.g. the methoxycarbonyloxymethyl, l-ethoxycarbonyloxyethyl and l-isopropoxycarbonyloxyethyl ester), the lactonyl esters (e.g. the phthalidyl ~$
; - 2 - ~ ~'77~Z3 and thiophthalidyl ester), the lower alko~ymethyl esters (e.g. the methoxymethyl ester) and the lower alXanoylamino-methyl esters (e.g. the acetamidomethyl ester). Other esters (e.g. the benzyl and cyanomethyl esters) can also be used.
Examples or salts of the compound of formula I-are alkali metal salts such as the sodium and potassium salt, the ammonium salt, alkaline earth metal salts such as the calcium salt, salts with organic bases such as salts wlth amines (e.g. salts with N-ethyl-piperidine, procaine, dibenzylamine, N,N'-dibenzylethylenediamine, alkylamines or dialkyi~mines) as well as salts with amino acids such as, for example, salts with arginine or lysine.
The compound o~ formula I also forms addition salts with organic or inorganic acids. Examples of such salts are hydrohalides (e.g. hydrochlorides, hydrobromides and hydroiodides) as well as other mineral acid salts such as sulphates, nitrates, phosphates and the like, alkylsulphonates and monoarylsulphonates such as ethanesulphonates, toluene-sulphonates, ben2enesulphonates and the like and also other organic acid salts such as acetates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates and the like.
The compound of formula I as well as its salts and readily hydrol~sable esters can be hydrated. The hydration ~' - 3 -can be effected in ~he course of the manufacturing process or can occur gradually as a result of the hygroscopic properties of an initlally anhydrous product.
The products in accordance with the in~ention can be present in the syn-isomeric form N~--CONH~
OCH~
or in the anti-isomeric form /
or as mixtures of these two forms. The syn-isomeric form : 10 or mixtures in which the syn-isomeric form predominates is/
are preferred.
The compound of formula I, i.e.
(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[(Z)-methoxy-imino]acetamido~-3-[[(2,5-dihydro-2-me~hyl-5-oxo-as--triazin-3-yl)thio~methyl]-8-oxo-5-~hia-1-azabicyclo[~.2.0~-:
,t~78~3 oct-2-ene-2-carboxylic acid, is preferred, as are its salts and the corresponding hydrates, the salts be.ing pharmaceutic-ally acceptable.
The abo~e cephaLosporin derivatives are manufac-tured in accord2nce with the i~vention by (a) cleaving off the protecting group R, and, if desired, also a carboxy protecting group which may be present, in a compound of the general formula H H
CH30N==~ CO~H I ~ N ~ q N ~ ~ ~ C~2 S ~ N ~ 0 RHN S
COOH
in ~hich R represents a cleavable protecting group and the carboxy group can be present in protected form, or (b) reacting a halide of the general rormula 1~ H
C H3 0 N=~--C O ~I H ~ 3 ~ N~'~
C o d~-~H~
C~O~
- 5 - ~ ~r~8'~3 in which ~- represents a halogen atom and the carboxy group can be present in protected form, with thiourea, or tc) for the manufacture of a readily hydrolysable ester of the carboxylic acid of formula I, subjecting this to a corresponding esterification, or (d) for the manufacture of salts or hydrates of tne compound of formula I or hydrates of these salts, converting the compound OI formula I into a salt or hydrate or into a hydrate of said salt.
If desired, the carboxy group present in the starti~g materials of formulae II and III can be protected; for example, by esterification to form a readily cleavable ester such as a silyl ester (e.g. the trimethylsilyl ester).
The readily hydrolysable esters mentioned above also come into consideration. The carboxy group can also be protected by salt forma~ion with an inorganic or tertiary organic base such as triethylamine. Possible R-protec~ing groups are, for example, protecting groups which are cleavable by acid hydrolysis such as, for example, tert butoxycarbonyl or trityl, or protecting groups which are cLeavable by basic 2i nydrolysis such as, for example, trifluoroacetyl. Pre-erred - 6 ~ 7~23 R-protecting groups are chloroacetyl, bromoacetyl and iodoacetyl, especially chloroacetyl. The last-mentioned protecting groups can be cleaved off by treatment with thiourea.
S The starting materials of formula II can be prepared, for example, by N-acylating the corresponding 7-amino compound, namely by reacting a compound of the formula H H
H2N ~ f CHz - S ~ ~ ~ IV
COOH
in which the carboxy group and/or the amino group can be present in protected form, with an acid of the general formula CH30N---v COOH V
11 ,~
RHN \S
- 7 ~ 77~23 in which R has the significance given above, or with a reactive functional derivative of this acid and, if desired, cleaving off a carboxy protecting group which may be present.
If desired, the carboxy group present in the 7-amino compound of formula IV can be protected in the manner mentioned above for the starting material of formula II
to be prepared. The amino group of the compound of formula IV can be protected, for example by a silyl protecting group such as trimethylsilyl.
As reactive functional derivatives of acids of formula V there come into consideration, for example, halides (i-e. chloridesr bromides and fluorides), azides, anhydrides, especially mixed anhydrides with strong acids, reactive esters (e.g. N-hydroxysuccinimide esters) and amides (e.g.
imidazolides).
The reaction of the 7-amino compound of formula IV
20 with an acid of formula V or a reactive functional derivative thereof can be carried out in a manner known per se. Thus, for example, a free acid of formula V can be condensed with one of the aforementioned esters corresponding to formula IV by means of a carbodiimide such as d cyclo-~ 8 ~ 77~3 hexylcarbodiimide in an inert solvent such as ethyl acetate,acetonitrile, dioxan, chloroform, methylene chloride, kenzene or dimethylformamide and subsequently the ester group can be cleaved off. Oxazolium salts (e.g~ N-ethyl~5-phenyl--isoxazolium-3'-sulphonate) can also be used as the condensation agent in place of carbodiimides.
According to another embodiment, a salt of an acid of formula IV (e.g. a trialkylammonium salt such as the triethylammonium salt) is reacted with a reactive functional derivative of an acid of formula V as mentioned above in an inert solvent (e.g. one of the solvents named above).
.
According to a further embodiment, an acid halide, preferably the chloride, of an acid of formula V is reacted with the amine of formula IV. The reaction is preferably carried out in the presence of an acid-binding agent, for example, in the presence of aqueous alkali, preferably sodium hydroxide, or in the presence of an alkali metal carbonate such as potassium carbonate or in the presence of a lower alkylated amine such as triethylamine. As the solvent there is preferably used water, optionally in admixture with an inert organic solvent such as tetrahydro-furan or dioxan. The reaction can also be carried out in an aprotic organic solvent such as, for example, dimethyl-formamide, dimethyl sulphoxide or hexamethylphosphoric acid - g ~ 7823 triamide. When a silylated startins material of formula IV
is used, the reaction is carried out in an anhydrous medium.
The reaction of the 7-amino compound of formula IV
with an acid of formula V or a reactive functional derivative thereof can conveniently be carried out at temperatures between about -40C and room temperature, for example at about 0-10C.
Starting materials of ~ormula II wherein R is not monohalogenated (as in bromo-, chloro andi.cdoacetyl) can also be prepared by thiolation, namely by reacting a compound of the general formula H H
CH30N '`--CONH--~S~
~CH2--Z VI
FF~I N S
CO~H
in which R is as R but cannot be mono-halogenated, z represents a leaving lS yroup and the carboxy group can be protected by salt formation with an inorganic or tertiary organic base, with a thiol of the formula - 10 ~L~778~:3 H3C ~
~ N VII
and, if desired, cleaving off a carb~xy protecting group which may be present.
As the leaving group Z in a compound of formula VI
there come into consideration, for example, halogens (e.g.
chlorine, bromine or iodine), acyloxy groups ~e.g. lower alkanoyloxy groups such as acetoxy), lower alkylsulphonyloxy or arylsulphonyloxy groups such as me~yloxy or tosyloxy, or the azido group.
The reaction of a compollnd of formula VI with the thiol of formula VII can be carried out in a manner known per se; for example, at a temperature between about 40C
and 80C, conveniently at about 60C, preferably in wa.er or in a buffer solution with a pH of about 6 to 7, preferably 6.5.
77~'23 ~ he carboxy group of the resulting compound of rormula II can subsequently be protected if desired (e.g. by salt formation or esterification).
The thiol of formula VII is in tautomeric equilibrium with the corresponding thione. Its preparation is described in Example 1.
In accordance with variant (a) of the process in accoxdance with the invention, the amino protecting group R in a starting material of formula II is cleaved off.
Protecting groups which are cleavable by acid hydrolysis are preferably removed with the aid of a lower alkanecarboxylic acid which may be halogenated. In particular, formic acid or trifluoroacetic acid is used. This cleavage is generally carried out at room temperature, although it can be carried out at a slightly higher or slightly lower temperature, for example, a temperature in the range of aboùt 0C to ~40C. Protecting groups which axe cleavable under alkaline conditions are generally hydrolysed with dilute aqueous caustic alkali at 0C to 30C. The chloroacetyl, bromo-acetyl and iodoacetyl protecting groups can be cleaved offby means of thiourea in acidic, neutral or alkaline medium at about 0-30C. Hydrogenolytic cleavage (e.g. cleavage of benzyl) is unsuitable in this case, since the oxime function is reduced to the amino sroup during the hydrogen olysis.
- 12 ~ 77~3 After carrying out process variant (a), a carbo~y protecting group which may be present in the reaction product can be cleaved off if desired. When the protecting group is a silyl group (silyl ester), this group can be cleaved orf especially readily by treating the reaction product with water. Lower alXanoyloxyalkyl, alkoxycarbonyloxyalkyl, lactonyl, alkoxymethyl and alkanoylaminomethyl esters are preferably cleaved enzymatically with the aid of a suitable esterase (at about 20-40C). When the carboxy group is protected by salt formation (e.g. with triethylamine), then the cleavage of this salt-forming protecting group can be carried out by treatment with acid. The acid which can be used for this purpose can be, for example, hydrochloric acid, sulphuric acid, phosphoric acid or citric acid.
lS The carboxy protecting group can be cleaved off in the same manner as just described also prior to the cleavage of the protecting group R.
The halide of formula III used in accordance with the invention can be prepared, for example, by reacting a compound of fcrmula IV with a halogenated carboxylic acid of the general formula CH30N==~ CCOH
CO
I VIII
- 13 - ~1'77~23 in which Y represents a halogen atom, or with a reactive derivative of this compound. The halogenated carboxylic acid of formula VIII is used either in free form in the presence o~ a condensation agent (e.g.
a N,N'-disubstituted carbodiimide such as N,N'-dicyclo-hexylcarbodiimide or an azolide compound such as N,~'--carbonyldiimidazole or N,N'-thionyldiimidazole) or also in the form of an acid halide such as th~ acid chloride or acid bromide, in the form of an acid anhydride such an acid anhydride with a carbonic acid monoester (e.g. with monomethyl carbonate or monoisopropyl carbonate) or in the form of an activated ester such as the p-nitrophenyl ester, 2,4-dinitro-phenyl ester, N-hydroxysuccinimide ester or N-hydroxy-phthalimide ester. The reaction is generally carried out in an inert organic solvent, for example in a halogenated hydrocarbon such as chloroform, dichloromethane or carbon tetrachloride, in an ether (e.g. tetrahydrofuran or dioxan), in dimethylformamide, dimethylacetamide, water or mixtures thereof. The reaction temperature lies mainly in the range of about -50C to +40C, preferably at about -10C to +10C.
The reaction of a halide of formula III with thiourea in accordance with the invention, variant (b) of the process in accordance with the invention, is preferably carried out in an inert solvent such as, for example, in a lower alXanol (e.g. ethanol), in a lower ketone such as acetone, in an ether such as tetrahydrofuran or dioxan, in dimethylformamide, 7~:3 dimethylacetamide, in water or in mixtures tnexeo~. The reaction temperature generally lies in the range of about 0C to 60C, preferably at room temperature. The chloride, bromide, fluoride or iodide can be used as the halide of formula III, the chloride or the bromide preferably being used. The free acid of formula III or, if desired, a salt thereof can be used, whereby the same salts as the aforementioned salts of the compound of formula I come into consideration.
In order to manufacture the readily hydrolysable esters of the carboxylic acid of formula I in accordance with variant (c), this is preferably reacted with the corresponding halide preferably with the iodide, containing the ester group. The reaction can be accelerated with the aid of a base, for example, an alkali metal hydroxide or carbonate or an organic amine such as triethylamine. The esterification i3 pre~erably carried out in an inert solvent such as dimethyl-acetamide, hexamethylphosphoric acid triamide, dimethyl sulphoxide or, preferably, dimethylformamide. The temperature preferably lies in the range of about 0-40C.
The manufacture of the salts and hydrates or the compound of formula I or the hydrates of these salts can be carried out in a manner known per se; for example, by reacting the carboxylic acid of formula I with an equivalent amount of the desired base, conveniently in a solvent such as water or in an organic solvent such as ethanol, methanol, acetone etc. The temperature at which the salt for~ation is carried out is not critical. It is generally carried out at room temperature, but it can also be carried out at a temperature slightly above or below room temperature (e.g.
in the range of 0C to ~50C).
The manufacture or the hydrates usually takes place automatically in the course of the manufacturing process or as a result of the hygroscopic properties of an initially anhydrous product. ~or the controlled manufacture of a hydrate, a completely or partially anhydrous product (carboxylic acid of formula I or ester, ether or salt thereof) can be exposed to a moist atmosphere (e.g. at about ~10C to ~40C).
The 7-amino compound of formula IV used above can be prepared starting from a compound of the formula H H
H2N~S~
C~z~~~ Z IX
COOH
in which Z represents a leaving group and the carboxy group can be protected by salt ~ormation ~ith an inorganic or tertiary organic base, ~7823 with the thiol of formula VII. The reaction can be carried out under the same conditions as those which have been , described for the reaction of the starting materials of formulae VI and VII. On th~ other hand, the compounds of formula VI can be prepared starting from a compound of formula IX and an acid of formula V or a reactive functional derivative thereof under the same conditions as have been described for the reaction of the compounds of formulae IV
and V.
The carboxy group and/or the amino group of the resulting compound of formula,IV can subsequently be protected if desired; for example, by esterifying the carboxy group or forming a salt thereon or by silylating the amino groupO
A syn/anti mixture of a compound of formula I which may be obtained,can be separated into the corresponding syn- and anti-forms in the customary manner, for example by recrystallisation or by chromatographical methods using a suitable solvent or solvent mixture.
The compounds of formulae I and II as well as the corresponding readily hydrolysable esters and salts or the hydrates of these products have antibiotic, especially bactericidal, activity. They possess a broad spectrum ot ` - 17 - ~ ~77~3 action against gram-positive bacteria (e.g. Staphylococci) and against gram-negative bacteria such as, for example, Haemophilus influenzae and Neisseria gonorrhoeae, as ~ell as against various ~-lactamase-forming gram-negative organisms such as Escherichia coli, Serratia marcescens, Pseudomonas aeruginosa, Proteus mirabilis and Proteus vulgaris.
The compounds of formulae I and II as well as the corresponding readily hydrolysable ester~ and salts or the hydrates of these products can be used for the treatment and prophylaxis of infectious diseases. A daily dosage of about 0.1 g to about 2 g comes into consideration for adults.
The parenteral administration of the compounds provided by the invention is especially preferred.
In order to demonstrate the antimicrobial activity of the aforementioned products (6R,7R)-7 [2-(2-amino-5--thiazolyl)-2-[(Z)-methoxyimino]acetamido]-3-[[(2,5-dihydro-
- ~ H3C
CH20N = C - CONH ~ S ~ N ~ I
1 N ~ ~ N ~ CH2 - S ~ N
as well as readily hydrolysable esters and salts of this compound and hydrates of the compound of formula I or of esters and salts thereof, when prepared by the process described hereinafter, wherein the esters and salts are pharmaceutically acceptable.
As readily hydrolysable esters of the compound of formula I there are to be understood the compound of formula I in which the carboxy group is present in the form of a readily hydrolysable ester group. Examples of such esters, which can be of the conventional type, are the lower alkanoyloxyalkyl ester (e.g. the acetoxymethyl, pivaloyloxymethyl, l-acetoxyethyl and l-pivaloyloxyethyl ester), the lower alkoxycarbonyloxyalkyl esters (e.g. the methoxycarbonyloxymethyl, l-ethoxycarbonyloxyethyl and l-isopropoxycarbonyloxyethyl ester), the lactonyl esters (e.g. the phthalidyl ~$
; - 2 - ~ ~'77~Z3 and thiophthalidyl ester), the lower alko~ymethyl esters (e.g. the methoxymethyl ester) and the lower alXanoylamino-methyl esters (e.g. the acetamidomethyl ester). Other esters (e.g. the benzyl and cyanomethyl esters) can also be used.
Examples or salts of the compound of formula I-are alkali metal salts such as the sodium and potassium salt, the ammonium salt, alkaline earth metal salts such as the calcium salt, salts with organic bases such as salts wlth amines (e.g. salts with N-ethyl-piperidine, procaine, dibenzylamine, N,N'-dibenzylethylenediamine, alkylamines or dialkyi~mines) as well as salts with amino acids such as, for example, salts with arginine or lysine.
The compound o~ formula I also forms addition salts with organic or inorganic acids. Examples of such salts are hydrohalides (e.g. hydrochlorides, hydrobromides and hydroiodides) as well as other mineral acid salts such as sulphates, nitrates, phosphates and the like, alkylsulphonates and monoarylsulphonates such as ethanesulphonates, toluene-sulphonates, ben2enesulphonates and the like and also other organic acid salts such as acetates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates and the like.
The compound of formula I as well as its salts and readily hydrol~sable esters can be hydrated. The hydration ~' - 3 -can be effected in ~he course of the manufacturing process or can occur gradually as a result of the hygroscopic properties of an initlally anhydrous product.
The products in accordance with the in~ention can be present in the syn-isomeric form N~--CONH~
OCH~
or in the anti-isomeric form /
or as mixtures of these two forms. The syn-isomeric form : 10 or mixtures in which the syn-isomeric form predominates is/
are preferred.
The compound of formula I, i.e.
(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[(Z)-methoxy-imino]acetamido~-3-[[(2,5-dihydro-2-me~hyl-5-oxo-as--triazin-3-yl)thio~methyl]-8-oxo-5-~hia-1-azabicyclo[~.2.0~-:
,t~78~3 oct-2-ene-2-carboxylic acid, is preferred, as are its salts and the corresponding hydrates, the salts be.ing pharmaceutic-ally acceptable.
The abo~e cephaLosporin derivatives are manufac-tured in accord2nce with the i~vention by (a) cleaving off the protecting group R, and, if desired, also a carboxy protecting group which may be present, in a compound of the general formula H H
CH30N==~ CO~H I ~ N ~ q N ~ ~ ~ C~2 S ~ N ~ 0 RHN S
COOH
in ~hich R represents a cleavable protecting group and the carboxy group can be present in protected form, or (b) reacting a halide of the general rormula 1~ H
C H3 0 N=~--C O ~I H ~ 3 ~ N~'~
C o d~-~H~
C~O~
- 5 - ~ ~r~8'~3 in which ~- represents a halogen atom and the carboxy group can be present in protected form, with thiourea, or tc) for the manufacture of a readily hydrolysable ester of the carboxylic acid of formula I, subjecting this to a corresponding esterification, or (d) for the manufacture of salts or hydrates of tne compound of formula I or hydrates of these salts, converting the compound OI formula I into a salt or hydrate or into a hydrate of said salt.
If desired, the carboxy group present in the starti~g materials of formulae II and III can be protected; for example, by esterification to form a readily cleavable ester such as a silyl ester (e.g. the trimethylsilyl ester).
The readily hydrolysable esters mentioned above also come into consideration. The carboxy group can also be protected by salt forma~ion with an inorganic or tertiary organic base such as triethylamine. Possible R-protec~ing groups are, for example, protecting groups which are cleavable by acid hydrolysis such as, for example, tert butoxycarbonyl or trityl, or protecting groups which are cLeavable by basic 2i nydrolysis such as, for example, trifluoroacetyl. Pre-erred - 6 ~ 7~23 R-protecting groups are chloroacetyl, bromoacetyl and iodoacetyl, especially chloroacetyl. The last-mentioned protecting groups can be cleaved off by treatment with thiourea.
S The starting materials of formula II can be prepared, for example, by N-acylating the corresponding 7-amino compound, namely by reacting a compound of the formula H H
H2N ~ f CHz - S ~ ~ ~ IV
COOH
in which the carboxy group and/or the amino group can be present in protected form, with an acid of the general formula CH30N---v COOH V
11 ,~
RHN \S
- 7 ~ 77~23 in which R has the significance given above, or with a reactive functional derivative of this acid and, if desired, cleaving off a carboxy protecting group which may be present.
If desired, the carboxy group present in the 7-amino compound of formula IV can be protected in the manner mentioned above for the starting material of formula II
to be prepared. The amino group of the compound of formula IV can be protected, for example by a silyl protecting group such as trimethylsilyl.
As reactive functional derivatives of acids of formula V there come into consideration, for example, halides (i-e. chloridesr bromides and fluorides), azides, anhydrides, especially mixed anhydrides with strong acids, reactive esters (e.g. N-hydroxysuccinimide esters) and amides (e.g.
imidazolides).
The reaction of the 7-amino compound of formula IV
20 with an acid of formula V or a reactive functional derivative thereof can be carried out in a manner known per se. Thus, for example, a free acid of formula V can be condensed with one of the aforementioned esters corresponding to formula IV by means of a carbodiimide such as d cyclo-~ 8 ~ 77~3 hexylcarbodiimide in an inert solvent such as ethyl acetate,acetonitrile, dioxan, chloroform, methylene chloride, kenzene or dimethylformamide and subsequently the ester group can be cleaved off. Oxazolium salts (e.g~ N-ethyl~5-phenyl--isoxazolium-3'-sulphonate) can also be used as the condensation agent in place of carbodiimides.
According to another embodiment, a salt of an acid of formula IV (e.g. a trialkylammonium salt such as the triethylammonium salt) is reacted with a reactive functional derivative of an acid of formula V as mentioned above in an inert solvent (e.g. one of the solvents named above).
.
According to a further embodiment, an acid halide, preferably the chloride, of an acid of formula V is reacted with the amine of formula IV. The reaction is preferably carried out in the presence of an acid-binding agent, for example, in the presence of aqueous alkali, preferably sodium hydroxide, or in the presence of an alkali metal carbonate such as potassium carbonate or in the presence of a lower alkylated amine such as triethylamine. As the solvent there is preferably used water, optionally in admixture with an inert organic solvent such as tetrahydro-furan or dioxan. The reaction can also be carried out in an aprotic organic solvent such as, for example, dimethyl-formamide, dimethyl sulphoxide or hexamethylphosphoric acid - g ~ 7823 triamide. When a silylated startins material of formula IV
is used, the reaction is carried out in an anhydrous medium.
The reaction of the 7-amino compound of formula IV
with an acid of formula V or a reactive functional derivative thereof can conveniently be carried out at temperatures between about -40C and room temperature, for example at about 0-10C.
Starting materials of ~ormula II wherein R is not monohalogenated (as in bromo-, chloro andi.cdoacetyl) can also be prepared by thiolation, namely by reacting a compound of the general formula H H
CH30N '`--CONH--~S~
~CH2--Z VI
FF~I N S
CO~H
in which R is as R but cannot be mono-halogenated, z represents a leaving lS yroup and the carboxy group can be protected by salt formation with an inorganic or tertiary organic base, with a thiol of the formula - 10 ~L~778~:3 H3C ~
~ N VII
and, if desired, cleaving off a carb~xy protecting group which may be present.
As the leaving group Z in a compound of formula VI
there come into consideration, for example, halogens (e.g.
chlorine, bromine or iodine), acyloxy groups ~e.g. lower alkanoyloxy groups such as acetoxy), lower alkylsulphonyloxy or arylsulphonyloxy groups such as me~yloxy or tosyloxy, or the azido group.
The reaction of a compollnd of formula VI with the thiol of formula VII can be carried out in a manner known per se; for example, at a temperature between about 40C
and 80C, conveniently at about 60C, preferably in wa.er or in a buffer solution with a pH of about 6 to 7, preferably 6.5.
77~'23 ~ he carboxy group of the resulting compound of rormula II can subsequently be protected if desired (e.g. by salt formation or esterification).
The thiol of formula VII is in tautomeric equilibrium with the corresponding thione. Its preparation is described in Example 1.
In accordance with variant (a) of the process in accoxdance with the invention, the amino protecting group R in a starting material of formula II is cleaved off.
Protecting groups which are cleavable by acid hydrolysis are preferably removed with the aid of a lower alkanecarboxylic acid which may be halogenated. In particular, formic acid or trifluoroacetic acid is used. This cleavage is generally carried out at room temperature, although it can be carried out at a slightly higher or slightly lower temperature, for example, a temperature in the range of aboùt 0C to ~40C. Protecting groups which axe cleavable under alkaline conditions are generally hydrolysed with dilute aqueous caustic alkali at 0C to 30C. The chloroacetyl, bromo-acetyl and iodoacetyl protecting groups can be cleaved offby means of thiourea in acidic, neutral or alkaline medium at about 0-30C. Hydrogenolytic cleavage (e.g. cleavage of benzyl) is unsuitable in this case, since the oxime function is reduced to the amino sroup during the hydrogen olysis.
- 12 ~ 77~3 After carrying out process variant (a), a carbo~y protecting group which may be present in the reaction product can be cleaved off if desired. When the protecting group is a silyl group (silyl ester), this group can be cleaved orf especially readily by treating the reaction product with water. Lower alXanoyloxyalkyl, alkoxycarbonyloxyalkyl, lactonyl, alkoxymethyl and alkanoylaminomethyl esters are preferably cleaved enzymatically with the aid of a suitable esterase (at about 20-40C). When the carboxy group is protected by salt formation (e.g. with triethylamine), then the cleavage of this salt-forming protecting group can be carried out by treatment with acid. The acid which can be used for this purpose can be, for example, hydrochloric acid, sulphuric acid, phosphoric acid or citric acid.
lS The carboxy protecting group can be cleaved off in the same manner as just described also prior to the cleavage of the protecting group R.
The halide of formula III used in accordance with the invention can be prepared, for example, by reacting a compound of fcrmula IV with a halogenated carboxylic acid of the general formula CH30N==~ CCOH
CO
I VIII
- 13 - ~1'77~23 in which Y represents a halogen atom, or with a reactive derivative of this compound. The halogenated carboxylic acid of formula VIII is used either in free form in the presence o~ a condensation agent (e.g.
a N,N'-disubstituted carbodiimide such as N,N'-dicyclo-hexylcarbodiimide or an azolide compound such as N,~'--carbonyldiimidazole or N,N'-thionyldiimidazole) or also in the form of an acid halide such as th~ acid chloride or acid bromide, in the form of an acid anhydride such an acid anhydride with a carbonic acid monoester (e.g. with monomethyl carbonate or monoisopropyl carbonate) or in the form of an activated ester such as the p-nitrophenyl ester, 2,4-dinitro-phenyl ester, N-hydroxysuccinimide ester or N-hydroxy-phthalimide ester. The reaction is generally carried out in an inert organic solvent, for example in a halogenated hydrocarbon such as chloroform, dichloromethane or carbon tetrachloride, in an ether (e.g. tetrahydrofuran or dioxan), in dimethylformamide, dimethylacetamide, water or mixtures thereof. The reaction temperature lies mainly in the range of about -50C to +40C, preferably at about -10C to +10C.
The reaction of a halide of formula III with thiourea in accordance with the invention, variant (b) of the process in accordance with the invention, is preferably carried out in an inert solvent such as, for example, in a lower alXanol (e.g. ethanol), in a lower ketone such as acetone, in an ether such as tetrahydrofuran or dioxan, in dimethylformamide, 7~:3 dimethylacetamide, in water or in mixtures tnexeo~. The reaction temperature generally lies in the range of about 0C to 60C, preferably at room temperature. The chloride, bromide, fluoride or iodide can be used as the halide of formula III, the chloride or the bromide preferably being used. The free acid of formula III or, if desired, a salt thereof can be used, whereby the same salts as the aforementioned salts of the compound of formula I come into consideration.
In order to manufacture the readily hydrolysable esters of the carboxylic acid of formula I in accordance with variant (c), this is preferably reacted with the corresponding halide preferably with the iodide, containing the ester group. The reaction can be accelerated with the aid of a base, for example, an alkali metal hydroxide or carbonate or an organic amine such as triethylamine. The esterification i3 pre~erably carried out in an inert solvent such as dimethyl-acetamide, hexamethylphosphoric acid triamide, dimethyl sulphoxide or, preferably, dimethylformamide. The temperature preferably lies in the range of about 0-40C.
The manufacture of the salts and hydrates or the compound of formula I or the hydrates of these salts can be carried out in a manner known per se; for example, by reacting the carboxylic acid of formula I with an equivalent amount of the desired base, conveniently in a solvent such as water or in an organic solvent such as ethanol, methanol, acetone etc. The temperature at which the salt for~ation is carried out is not critical. It is generally carried out at room temperature, but it can also be carried out at a temperature slightly above or below room temperature (e.g.
in the range of 0C to ~50C).
The manufacture or the hydrates usually takes place automatically in the course of the manufacturing process or as a result of the hygroscopic properties of an initially anhydrous product. ~or the controlled manufacture of a hydrate, a completely or partially anhydrous product (carboxylic acid of formula I or ester, ether or salt thereof) can be exposed to a moist atmosphere (e.g. at about ~10C to ~40C).
The 7-amino compound of formula IV used above can be prepared starting from a compound of the formula H H
H2N~S~
C~z~~~ Z IX
COOH
in which Z represents a leaving group and the carboxy group can be protected by salt ~ormation ~ith an inorganic or tertiary organic base, ~7823 with the thiol of formula VII. The reaction can be carried out under the same conditions as those which have been , described for the reaction of the starting materials of formulae VI and VII. On th~ other hand, the compounds of formula VI can be prepared starting from a compound of formula IX and an acid of formula V or a reactive functional derivative thereof under the same conditions as have been described for the reaction of the compounds of formulae IV
and V.
The carboxy group and/or the amino group of the resulting compound of formula,IV can subsequently be protected if desired; for example, by esterifying the carboxy group or forming a salt thereon or by silylating the amino groupO
A syn/anti mixture of a compound of formula I which may be obtained,can be separated into the corresponding syn- and anti-forms in the customary manner, for example by recrystallisation or by chromatographical methods using a suitable solvent or solvent mixture.
The compounds of formulae I and II as well as the corresponding readily hydrolysable esters and salts or the hydrates of these products have antibiotic, especially bactericidal, activity. They possess a broad spectrum ot ` - 17 - ~ ~77~3 action against gram-positive bacteria (e.g. Staphylococci) and against gram-negative bacteria such as, for example, Haemophilus influenzae and Neisseria gonorrhoeae, as ~ell as against various ~-lactamase-forming gram-negative organisms such as Escherichia coli, Serratia marcescens, Pseudomonas aeruginosa, Proteus mirabilis and Proteus vulgaris.
The compounds of formulae I and II as well as the corresponding readily hydrolysable ester~ and salts or the hydrates of these products can be used for the treatment and prophylaxis of infectious diseases. A daily dosage of about 0.1 g to about 2 g comes into consideration for adults.
The parenteral administration of the compounds provided by the invention is especially preferred.
In order to demonstrate the antimicrobial activity of the aforementioned products (6R,7R)-7 [2-(2-amino-5--thiazolyl)-2-[(Z)-methoxyimino]acetamido]-3-[[(2,5-dihydro-
-2-methyl-5-oxo-as-triazin-3~yl)thio]methyl]-8-oxo-5-thia--l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt was tested for its activity in vitro a~ainst various pathogenic organisms. The corresponding minimum inhibitory concentrations (MIC; ~g/ml) are compiled hereinafter:
- - 18 - ~ ~77~3 Pathogenic organism MIC
.. ... ~ _ Escherichia coli *) 0.04 Serratia marcescens *) 0.16 Enterobacter cloacae *) 2.5 Proteus mirabilis *) 0.04 Proteus vulgaris *) 0.02 Pseudomonas aeruginosa strain 1*) 40 strain 2*) 40 Haemophilus influenzae 0.02 Neisseria gonorrhoeae 0.02 Staphylococcus aureus 2.5 *) ~-lactamase-forming strain Toxicity .... _ _ .__ _ _ , Test substance _.._ . _.
oo, mg/ks i . v 1000 s.c. >5000 p.o. >5000 - 1 9 ~ 3 The products provided Dy the invention can be used as medicaments, for example, in the form of pharmaceutical preparations which contain them in admixture with a pharma-ceutical, organic or inorganic inert carrier materiaL which is suitable for enteral of parenteral administration such as, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, Vaseline etc. The pharmaceutical preparations can be made up in solid form (e.g. as tablets, dragées, suppositories or capsules) or in liquid form (e.g. as solutions, suspensions or emulsions). If necessary, th~y can be sterilised and/or can contain adjuvants such as preserving, stabilising, wetting or emulsifying agents, salts for varying the osmotic pressure, anaesthetics or buffers.
They can also contain still other therapeutically valuable substances. The compound of ormula I and its salts of hydrates are preferably administered parenterally and for this purpose are preferably prepared as lyophilisates or dry powders for dilution with customary agents such as water or isotonic sodium chloride solution. The readily hydrolysable esters of the compound of formula I and their salts or hydrates also come into consideration for enteral administration.
- 20 - ~ ~77~3 In the following Examples, which illustrate the present invention, all temperatures are degrees Centigrade.
Example 1 (6R,7R)-7-[2-(2-Amino-4-thia201yl)-2-[(Z)-methoxyimino]-s acetamido]-3-[[(2,5 dihydro-2-methyl-5-oxo-as-triazin-3-- l)~thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-Y . .__ -2-carboxylic acid sodium salt 61 g of (6R,7R)-7-[2-(chloroacetamido-4-thiazolyl)--2-[(Z)-methoxyimino]acetamido]-3-[[(2,5-dihydro-2-methyl--5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic a~id are treated in 1.5 1 of water with 30.4 g of thiourea and, while gassing with nitrogen and stirring, held for 20 hours at a pH-value of 7.0 with lN sodium hydroxide via an autotitrator. The pH--value is adjusted to 3.75 by the dropwise addition of lN hydrochloric acid while stirring. The separated precipitate is filtered off under suction and rejected. Now, the filtrate is adjusted to a pH-value of 3.0 with lN hydro-chloric acid while stirring, the precipitate is flltered off under suction, washed with water, ethanol and petroleum ether and dried. The crude product obtained is suspended in 90 ml of acetone/water ~1:1), treated w1th 45 ml of a 2N
solution of sodi~m 2-ethylcaproa.e in athyl acetate, stirred - 21 ~ 778Z3 until completa solution has occurred and thereafter precipitated by dropwise addition into 800 ml of acetone while stirring. The sodium salt is filtered off under suction, washed with acetone, ether and petroleum ether and dried.
For further purification, the substance is dissolved in 800 ml of methanol while stirring and filtered off from a small amount of undissolved substance. The filtrate is treated with active charcoal, filtered, evaporated to ca 400 ml in vacuo and filtered off from a small amount of precipitated substance.
The filtrate is treated dropwise with 1.6 1 of ethyl acetate to bring about precipitation, and the precipitate is filtered off under suction, washed with ethyl acetate, ether and petroleum ether and dried. There is obtained (6R,7R)-7--~2-(2-amino-4-thiazolyl)-2-[(Z)-methoxyimino]acetamido]-3--[[(2,5-dihydro-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]--8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-carboxylic acid sodium salt; m.p. from 192 (slow decomposition), [a]25 -135 (c = 1 in water).
The (6R,7R)-7-[2-(chloroacetamido-4-thiazolyl)-2-[(Z)--methoxyimino]acetamido]-3-[[(2,5-dihydro-2-methyl-5-oxo--as-triazin-3-yl(thio]methyl]-8-oxo-S-thia-l-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid used as the starting material can be prepared as follows:
- 22 ~ 7~3 2-Meth l-S-oxo-3-thioxo-2,3,4,5-as-triazine _ Y
34 g of 2-methyl-thiosemicarbazide are introducea portionwise into a solution of 80.8 g of glyoxylic acid hydrate in 450 ml of dimethylformamide. The suspension is stirred at 80 for 45 minutes. The reaction mixture is cooled, treated with 2~5 1 of water and the suspension is stirred at 0 for 1 hour. After filtration under suction, washing with water and drying, there is obtained the 2--methyl-thiosemicarbazone of glyoxylic acid, m.p. 204-205 (decomposition). This substance is introduced while stirring into a solution of 74 g o~ sodium carbonate in 700 ml of water and thereafter heated at 9S-98 for 3 hours while stirring. The solution is cooled to 5 and adjusted to a pH-value of 2 with stirring and dropwise addition of concentrated hydrochloric acid. After suction filtration, washing with ice/water and drying, there is obtained 2-methyl-5-oxo-3-thioxo-2,3,4,5-as-triazine, m.p.
221-222.
(6R,7R)-7~Amino-3-[[(2,5-dihydro-2-methyl-5-o~o-as-triazin-
- - 18 - ~ ~77~3 Pathogenic organism MIC
.. ... ~ _ Escherichia coli *) 0.04 Serratia marcescens *) 0.16 Enterobacter cloacae *) 2.5 Proteus mirabilis *) 0.04 Proteus vulgaris *) 0.02 Pseudomonas aeruginosa strain 1*) 40 strain 2*) 40 Haemophilus influenzae 0.02 Neisseria gonorrhoeae 0.02 Staphylococcus aureus 2.5 *) ~-lactamase-forming strain Toxicity .... _ _ .__ _ _ , Test substance _.._ . _.
oo, mg/ks i . v 1000 s.c. >5000 p.o. >5000 - 1 9 ~ 3 The products provided Dy the invention can be used as medicaments, for example, in the form of pharmaceutical preparations which contain them in admixture with a pharma-ceutical, organic or inorganic inert carrier materiaL which is suitable for enteral of parenteral administration such as, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, Vaseline etc. The pharmaceutical preparations can be made up in solid form (e.g. as tablets, dragées, suppositories or capsules) or in liquid form (e.g. as solutions, suspensions or emulsions). If necessary, th~y can be sterilised and/or can contain adjuvants such as preserving, stabilising, wetting or emulsifying agents, salts for varying the osmotic pressure, anaesthetics or buffers.
They can also contain still other therapeutically valuable substances. The compound of ormula I and its salts of hydrates are preferably administered parenterally and for this purpose are preferably prepared as lyophilisates or dry powders for dilution with customary agents such as water or isotonic sodium chloride solution. The readily hydrolysable esters of the compound of formula I and their salts or hydrates also come into consideration for enteral administration.
- 20 - ~ ~77~3 In the following Examples, which illustrate the present invention, all temperatures are degrees Centigrade.
Example 1 (6R,7R)-7-[2-(2-Amino-4-thia201yl)-2-[(Z)-methoxyimino]-s acetamido]-3-[[(2,5 dihydro-2-methyl-5-oxo-as-triazin-3-- l)~thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-Y . .__ -2-carboxylic acid sodium salt 61 g of (6R,7R)-7-[2-(chloroacetamido-4-thiazolyl)--2-[(Z)-methoxyimino]acetamido]-3-[[(2,5-dihydro-2-methyl--5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic a~id are treated in 1.5 1 of water with 30.4 g of thiourea and, while gassing with nitrogen and stirring, held for 20 hours at a pH-value of 7.0 with lN sodium hydroxide via an autotitrator. The pH--value is adjusted to 3.75 by the dropwise addition of lN hydrochloric acid while stirring. The separated precipitate is filtered off under suction and rejected. Now, the filtrate is adjusted to a pH-value of 3.0 with lN hydro-chloric acid while stirring, the precipitate is flltered off under suction, washed with water, ethanol and petroleum ether and dried. The crude product obtained is suspended in 90 ml of acetone/water ~1:1), treated w1th 45 ml of a 2N
solution of sodi~m 2-ethylcaproa.e in athyl acetate, stirred - 21 ~ 778Z3 until completa solution has occurred and thereafter precipitated by dropwise addition into 800 ml of acetone while stirring. The sodium salt is filtered off under suction, washed with acetone, ether and petroleum ether and dried.
For further purification, the substance is dissolved in 800 ml of methanol while stirring and filtered off from a small amount of undissolved substance. The filtrate is treated with active charcoal, filtered, evaporated to ca 400 ml in vacuo and filtered off from a small amount of precipitated substance.
The filtrate is treated dropwise with 1.6 1 of ethyl acetate to bring about precipitation, and the precipitate is filtered off under suction, washed with ethyl acetate, ether and petroleum ether and dried. There is obtained (6R,7R)-7--~2-(2-amino-4-thiazolyl)-2-[(Z)-methoxyimino]acetamido]-3--[[(2,5-dihydro-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]--8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-carboxylic acid sodium salt; m.p. from 192 (slow decomposition), [a]25 -135 (c = 1 in water).
The (6R,7R)-7-[2-(chloroacetamido-4-thiazolyl)-2-[(Z)--methoxyimino]acetamido]-3-[[(2,5-dihydro-2-methyl-5-oxo--as-triazin-3-yl(thio]methyl]-8-oxo-S-thia-l-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid used as the starting material can be prepared as follows:
- 22 ~ 7~3 2-Meth l-S-oxo-3-thioxo-2,3,4,5-as-triazine _ Y
34 g of 2-methyl-thiosemicarbazide are introducea portionwise into a solution of 80.8 g of glyoxylic acid hydrate in 450 ml of dimethylformamide. The suspension is stirred at 80 for 45 minutes. The reaction mixture is cooled, treated with 2~5 1 of water and the suspension is stirred at 0 for 1 hour. After filtration under suction, washing with water and drying, there is obtained the 2--methyl-thiosemicarbazone of glyoxylic acid, m.p. 204-205 (decomposition). This substance is introduced while stirring into a solution of 74 g o~ sodium carbonate in 700 ml of water and thereafter heated at 9S-98 for 3 hours while stirring. The solution is cooled to 5 and adjusted to a pH-value of 2 with stirring and dropwise addition of concentrated hydrochloric acid. After suction filtration, washing with ice/water and drying, there is obtained 2-methyl-5-oxo-3-thioxo-2,3,4,5-as-triazine, m.p.
221-222.
(6R,7R)-7~Amino-3-[[(2,5-dihydro-2-methyl-5-o~o-as-triazin-
-3-yl)thio]met ~ ~5-thia-1-azabicyclo[4.2.0~oct-2--ene-2-carboxylic acid 27.2 g o~ 7-amino-cephalosporanic acid are treated in 200 ml of water while s-tirring first of all portionwise with 23.1 g or sodium hydrogen carbonate and thereafter - 23 - ~ ~77823 with 21.5 g of 2-methyl-5-oxo-3-thioxo-2,3,4,5-as-triazir.e.
subsequently, the mixture is heated at 60 for 5 hours while gassing with nitrogen. The solution is cooled to 5, adjusted to a pH-value of 3.5 with concentrated hydrochloric acid, the precipitated substance is filtered off, washed with water and stirred twice with 230 ml of methanol each time, filtered off, washed with methanol and ether and dried in vacuo. There is obtained (6R,7R)-7~amino-3-[[(2,5-dihydro--2-methyl-5-o~o-as-triaxin-3-yl)thio]methyl]-8-oxo-5--thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, m.p.
from 195 (decomposltion), which is further reacted without additional purification.
(6R,7R)-7-[2-(Chloroacetamido-4-thiazol~l)-2-[(Z)-methoxy-imino]acetamido-3-C[(2,5-dihydro-2-methyl-5-oxo-as-triazin--3-yl)thio]methyl]-8-oxo-5-thia-l-a7abicyclo[4.2.0]oct-2--ene-2-carboxylic acid 63 ml of N,N'-dimethylformamide are added dropwise to a suspension, cooled to -20, of 34.5 g of phosphorus pentachloride in 500 ml of dichloromethane, the mi~ture is stirred at -15 for 10 minutes, thereafter cooled to -25, treated with 46 g of 2-(2-chloroacetamido-4-thiazolyl)-2--methoxyimino-acetic acid (s~yn form) and stirred at -15 for 45 minutes. The solution is cooled to -30 and mi~ed with 50 g of ice, whereby the temperature rises to -1~.
- 2~ 778~3 The mixture is stixred at -15 for 10 minutes and then the dichloromethane solution is separated. It is cooled to -15 and used immediately for the following acylation.
Meanwhile, 61 g of (6R,7R)-7-amino-3-[[2,5-dihydro--2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia--l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid are dissolved in ~00 ml of water at a pH-value of 7. 8 via an autotitrator by the dropwise addition of 2N sodium hydroxide while stirring and cooled to 0. At this temperature there is added dropwise within 45 minutes the above (cooled to -15) dichloromethane solution of the acid chloride and a pH-value or 7.8-8.0 is maintained by the simultaneous dropwise addition of 2N sodium hydroxide via an autotitrator. The mixt~re is subsequently stirred for a further 30 minutes at 5 and for 1 hour at 20. The solution is treated with 500 ml of n-butanol and 500 ml of dichloromethane, whereafter it is adjusted to a pH-value of 7 with citric acid, stirred for 5 minutes at this pH-value and subsequently filtered in vacuo. The or~anic phase is separated, washed three times with 200 ml of water each time, treated with active charcoal, filtered off and evaporated in vacuo at 55 to ca 200 ml. The suspension obtained is cooled to 20 and filtered in ~acuo. There is obtained a first fraction o~ solid (6R,7R)-7-~2-(chloro-acetamido-4-thiazolyl)-2-[(Z)-methoxyimino]-acetamido]-3--[[(2,5-dihydro-2-methyl-5~oxo-as-triazin-3-yl)thio]methyl]--8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
_ ~5 _ ~ ~77~3 The mother liquor is evaporated to 100 ml in vacuo, mixed with 100 ml of ether and yields, after suction ~iltration, a second fraction of the mentioned acid. Both fractions are dissolved together in 2 1 of acetone while stirring within 15 minutes and insolubles are filtered of~. 300 ml of butyl acetate are added to the filtrate and the acetone is distilled off in vacuo until the substance crystallises.
There is obtained (6R,7R)-7-[2-(chloroacetamido-4-thiazolyl)--2-C(Z)-methoxyimino]-acetamido]-3-[[(2,5-dihydro-2-methyl--5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-aza~icyclo-[4.2.0]oct-2-ene-2-carboxylic acid, m.p. from 173 (decomposition), ~25 = -238.7~ (c = 1 in dimethylformamide).
The product is uniform in accordance with thin-layer chromatography in the system n-propanolJacetic acid/~ater 55:15:30 and is further reacted without addi.ional purification.
Example_2 Meth~lene (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2~[(Z~--methoxyimino]acetamido]-3-[[(2,5-dihydro-2-methvl-5-oxo--as-triazin-3-yl)thio]methyli-8-oxo-5-thia-1-azabicyc~o-[4.2.0]oct-2-ene-2-carboxylate pivalate 8 g of (6R,tR)-7-[2-(2-amino-4-thiazolyl)-2-[(Z)--methoxyimino]ace.amido]-3-[[(2,5-dihydro-2-me~nyl-5-oxo-~ - 26 - ~ ~77~3 -as-triazin-3-yl)thio]methyl]-8-oxo-S-thia l-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid sodium salt are dissoLved in 80 ml of dimethylformamide, cooled to 0, treated with 6 g of pivaloyloxymethyl iodide and stirred at 0 for 30 minutes. The solution is precipitated in ice/water, the precipitate is filtered of~ in vacuo, dissolved in ethyl acetate with the addition of some methanol, washed with sodium hydrogen carbonate solution and sodium chloride solution, dried with magnesium sulphate and evaporated in vacuo until crystallisation begins. The crystallisation is completed by the addition of a mixture of ether/petroleum ether 1:1. The substance is filtered off and subsequently chromatographed over silica gel with benzene/methanol 4:1. The uniform fractions are combined, evaporated in vacuo and finally crystallised from chloroform/
ether. There is obtained methylene (6R,7R)-7-[2-(2-amino-
subsequently, the mixture is heated at 60 for 5 hours while gassing with nitrogen. The solution is cooled to 5, adjusted to a pH-value of 3.5 with concentrated hydrochloric acid, the precipitated substance is filtered off, washed with water and stirred twice with 230 ml of methanol each time, filtered off, washed with methanol and ether and dried in vacuo. There is obtained (6R,7R)-7~amino-3-[[(2,5-dihydro--2-methyl-5-o~o-as-triaxin-3-yl)thio]methyl]-8-oxo-5--thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, m.p.
from 195 (decomposltion), which is further reacted without additional purification.
(6R,7R)-7-[2-(Chloroacetamido-4-thiazol~l)-2-[(Z)-methoxy-imino]acetamido-3-C[(2,5-dihydro-2-methyl-5-oxo-as-triazin--3-yl)thio]methyl]-8-oxo-5-thia-l-a7abicyclo[4.2.0]oct-2--ene-2-carboxylic acid 63 ml of N,N'-dimethylformamide are added dropwise to a suspension, cooled to -20, of 34.5 g of phosphorus pentachloride in 500 ml of dichloromethane, the mi~ture is stirred at -15 for 10 minutes, thereafter cooled to -25, treated with 46 g of 2-(2-chloroacetamido-4-thiazolyl)-2--methoxyimino-acetic acid (s~yn form) and stirred at -15 for 45 minutes. The solution is cooled to -30 and mi~ed with 50 g of ice, whereby the temperature rises to -1~.
- 2~ 778~3 The mixture is stixred at -15 for 10 minutes and then the dichloromethane solution is separated. It is cooled to -15 and used immediately for the following acylation.
Meanwhile, 61 g of (6R,7R)-7-amino-3-[[2,5-dihydro--2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia--l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid are dissolved in ~00 ml of water at a pH-value of 7. 8 via an autotitrator by the dropwise addition of 2N sodium hydroxide while stirring and cooled to 0. At this temperature there is added dropwise within 45 minutes the above (cooled to -15) dichloromethane solution of the acid chloride and a pH-value or 7.8-8.0 is maintained by the simultaneous dropwise addition of 2N sodium hydroxide via an autotitrator. The mixt~re is subsequently stirred for a further 30 minutes at 5 and for 1 hour at 20. The solution is treated with 500 ml of n-butanol and 500 ml of dichloromethane, whereafter it is adjusted to a pH-value of 7 with citric acid, stirred for 5 minutes at this pH-value and subsequently filtered in vacuo. The or~anic phase is separated, washed three times with 200 ml of water each time, treated with active charcoal, filtered off and evaporated in vacuo at 55 to ca 200 ml. The suspension obtained is cooled to 20 and filtered in ~acuo. There is obtained a first fraction o~ solid (6R,7R)-7-~2-(chloro-acetamido-4-thiazolyl)-2-[(Z)-methoxyimino]-acetamido]-3--[[(2,5-dihydro-2-methyl-5~oxo-as-triazin-3-yl)thio]methyl]--8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
_ ~5 _ ~ ~77~3 The mother liquor is evaporated to 100 ml in vacuo, mixed with 100 ml of ether and yields, after suction ~iltration, a second fraction of the mentioned acid. Both fractions are dissolved together in 2 1 of acetone while stirring within 15 minutes and insolubles are filtered of~. 300 ml of butyl acetate are added to the filtrate and the acetone is distilled off in vacuo until the substance crystallises.
There is obtained (6R,7R)-7-[2-(chloroacetamido-4-thiazolyl)--2-C(Z)-methoxyimino]-acetamido]-3-[[(2,5-dihydro-2-methyl--5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-aza~icyclo-[4.2.0]oct-2-ene-2-carboxylic acid, m.p. from 173 (decomposition), ~25 = -238.7~ (c = 1 in dimethylformamide).
The product is uniform in accordance with thin-layer chromatography in the system n-propanolJacetic acid/~ater 55:15:30 and is further reacted without addi.ional purification.
Example_2 Meth~lene (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2~[(Z~--methoxyimino]acetamido]-3-[[(2,5-dihydro-2-methvl-5-oxo--as-triazin-3-yl)thio]methyli-8-oxo-5-thia-1-azabicyc~o-[4.2.0]oct-2-ene-2-carboxylate pivalate 8 g of (6R,tR)-7-[2-(2-amino-4-thiazolyl)-2-[(Z)--methoxyimino]ace.amido]-3-[[(2,5-dihydro-2-me~nyl-5-oxo-~ - 26 - ~ ~77~3 -as-triazin-3-yl)thio]methyl]-8-oxo-S-thia l-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid sodium salt are dissoLved in 80 ml of dimethylformamide, cooled to 0, treated with 6 g of pivaloyloxymethyl iodide and stirred at 0 for 30 minutes. The solution is precipitated in ice/water, the precipitate is filtered of~ in vacuo, dissolved in ethyl acetate with the addition of some methanol, washed with sodium hydrogen carbonate solution and sodium chloride solution, dried with magnesium sulphate and evaporated in vacuo until crystallisation begins. The crystallisation is completed by the addition of a mixture of ether/petroleum ether 1:1. The substance is filtered off and subsequently chromatographed over silica gel with benzene/methanol 4:1. The uniform fractions are combined, evaporated in vacuo and finally crystallised from chloroform/
ether. There is obtained methylene (6R,7R)-7-[2-(2-amino-
-4-thiazolyl)-2-[(Z)-methoxyimino]acetamido]~3-[[(2,5~
-dihydro-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-
-dihydro-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-
-5-thia-1-azabicyclo[4.2.0]oct-2-ane-2-carboxylate pivalate.
M.p. 149 (decomposition), [a]25 = -173 (c = 1 in dimethyl-formamide).
Example 3 Preparation of dry am~poules for intramuscular administration:
~ ` \
- 27 ~ 8~
A lyophilisate of 1 g of the active substance is prepared in the customary manner and ~illed into an ampoule.
Prior to the administration, the lyophilisate is treated with 2.5 ml of a 2~ aqueous lidocaine hydrochloride solution.
M.p. 149 (decomposition), [a]25 = -173 (c = 1 in dimethyl-formamide).
Example 3 Preparation of dry am~poules for intramuscular administration:
~ ` \
- 27 ~ 8~
A lyophilisate of 1 g of the active substance is prepared in the customary manner and ~illed into an ampoule.
Prior to the administration, the lyophilisate is treated with 2.5 ml of a 2~ aqueous lidocaine hydrochloride solution.
Claims (11)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Process for the manufacture of a cephalosporin derivative of the formula I
or a pharmaceutically acceptable readily hydrolysable ester or a pharmaceutically acceptable salt of this compound and a hydrate of the compound of formula I or of the ester or the salt thereof, which process comprises (a) cleaving off the protecting group R, and, if desired, a carboxy protecting group which may be present, in a compound of the general formula II
in which R represents a cleavable protecting group and the carboxy group can be present in protected form, or (b) reacting a halide of the general formula III
in which Y represents a halogen atom and the carboxy group can be present in protected form, with thiourea, or (c) for the manufacture of a pharmaceutically acceptable readily hydrolysable ester of the carboxylic acid of formula I, subjecting the acid to a corresponding esterification, or (d) for the manufacture of a pharmaceutically acceptable salt or a hydrate of the compound of formula I or a hydrate of the salt, converting the compound of formula I into a pharmaceutically acceptable salt or hydrate or into a hydrate of said salt.
or a pharmaceutically acceptable readily hydrolysable ester or a pharmaceutically acceptable salt of this compound and a hydrate of the compound of formula I or of the ester or the salt thereof, which process comprises (a) cleaving off the protecting group R, and, if desired, a carboxy protecting group which may be present, in a compound of the general formula II
in which R represents a cleavable protecting group and the carboxy group can be present in protected form, or (b) reacting a halide of the general formula III
in which Y represents a halogen atom and the carboxy group can be present in protected form, with thiourea, or (c) for the manufacture of a pharmaceutically acceptable readily hydrolysable ester of the carboxylic acid of formula I, subjecting the acid to a corresponding esterification, or (d) for the manufacture of a pharmaceutically acceptable salt or a hydrate of the compound of formula I or a hydrate of the salt, converting the compound of formula I into a pharmaceutically acceptable salt or hydrate or into a hydrate of said salt.
2. Process according to claim 1 wherein step (a) or step (b) or steps (a) and (b) are carried out.
3. Process according to claim 1 for the manufacture of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[(Z)-methoxyaamino]acetamido]-3-[[(2,5-dihydro-2-methyl-5-oxo-as-triazin-3-yl)thhio]methyl]-8-oxo-5-thia-1-azabicvclo[4.2.0]oct-2-ene-2-carboxyllic acid or a pharmaceutically acceptable salt of this compound or a hydrate of this compound or the salt, characterized in that a starting compound of formula I is subjected to alternative (a) of claim 1, or a starting compound of formula III is subjected to alternative (b) of claim 1, or, when required, alternative (d) of claim 1 is carried out.
4. Process according to claim 1 for the manufacture of the pivaloyloxymethyl ester of the carboxylic acid defined in claim 1 characterized in that said carboxylic acid is reacted with a pivaloyloxymethyl halide.
5. A cephalosporin derivative of the formula I
or a pharmaceutically acceptable readily hydrolysable ester or a pharmaceutically acceptable salt of this compound and a hydrate of the compound of formula I or of the ester or the salt thereof, whenever prepared according to the process as claimed in claim 1 or by an obvious chemical equivalent thereof.
or a pharmaceutically acceptable readily hydrolysable ester or a pharmaceutically acceptable salt of this compound and a hydrate of the compound of formula I or of the ester or the salt thereof, whenever prepared according to the process as claimed in claim 1 or by an obvious chemical equivalent thereof.
6. (6R,7R)-7-[2-(2-Amino-4-thiazolyl)-2-[(Z)-methoxyiimino]-acetamido]-3-[[(2,5-dihydro-2-methyl-5-oxo-as-triaazin-3-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid or a pharmaceutically acceptable salt of this compound or a hydrate of this compound or the salt, whenever prepared according to the process as claimed in claim 3 or by an obvious chemical equivalent thereof.
7. The pivaloyloxymethyl ester of the carboxylic acid defined in claim 5, whenever prepared according to the process as claimed in claim 4 or by an obvious chemical equivalent thereof.
8. Process for the manufacture of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[(Z)-methoxyimino]acetamido]-3-[[(22,5-dihydro-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5--thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid or a pharmaceutically acceptable salt of this compound or a hydrate of this compound or the salt, which process comprises:
(1) cleaving off the protective chloroacetyl group in (6R,7R)-7-[2-(chloroacetamido-4-thiazolyl)-2-[(Z)--methoxyimino]-acetamido]-3-[[(2,5-dihydro-2-methyl-5-oxo-as-triaazin-3-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene--2-carboxylic acid, and if required, converting the resulting compound into a pharmaceutically acceptable salt or hydrate thereof or into a hydrate of the salt.
(1) cleaving off the protective chloroacetyl group in (6R,7R)-7-[2-(chloroacetamido-4-thiazolyl)-2-[(Z)--methoxyimino]-acetamido]-3-[[(2,5-dihydro-2-methyl-5-oxo-as-triaazin-3-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene--2-carboxylic acid, and if required, converting the resulting compound into a pharmaceutically acceptable salt or hydrate thereof or into a hydrate of the salt.
9. Process according to claim 8, wherein the cleavage of the protective group is conducted using thiourea in water.
10. Process according to claim 9, wherein the starting material is prepared by:
converting 2-(2-chloroacetamido-4-thiazolyl)-2-methoxy-imino-acetic acid (syn form) to its acid chloride, and reacting the acid chloride with (6R,7R)-7-amino-3-[[2,5-dihydro-2-methyl-5-oxo-as-triazln-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
converting 2-(2-chloroacetamido-4-thiazolyl)-2-methoxy-imino-acetic acid (syn form) to its acid chloride, and reacting the acid chloride with (6R,7R)-7-amino-3-[[2,5-dihydro-2-methyl-5-oxo-as-triazln-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
11. Process according to claim 8, 9 or 10, wherein the desired compound obtained by cleaving off the protective group is converted to its sodium salt.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH2327/80 | 1980-03-25 | ||
| CH232780 | 1980-03-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1177823A true CA1177823A (en) | 1984-11-13 |
Family
ID=4231218
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000373267A Expired CA1177823A (en) | 1980-03-25 | 1981-03-18 | Cephalosporin derivatives |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0036650A3 (en) |
| JP (1) | JPS56145291A (en) |
| AU (1) | AU536771B2 (en) |
| CA (1) | CA1177823A (en) |
| DK (1) | DK132981A (en) |
| IL (1) | IL62433A0 (en) |
| NZ (1) | NZ196552A (en) |
| ZA (1) | ZA811845B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5026843A (en) * | 1989-05-23 | 1991-06-25 | S.B.D. Synthetic And Biological Dvlpmnts. S.R.L. | Process for the preparation of ceftriaxone |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4200745A (en) * | 1977-12-20 | 1980-04-29 | Eli Lilly And Company | 7[2-(2-Aminothiazol-4-yl)-2-alkoxyimino]acetamido 3[4-alkyl-5-oxo-6-hydroxy-3,4 dihydro 1,2,4-triazin 3-yl]thio methyl cephalosporins |
| MC1259A1 (en) * | 1978-05-30 | 1980-01-14 | Hoffmann La Roche | ACYL DERIVATIVES |
-
1981
- 1981-03-18 AU AU68512/81A patent/AU536771B2/en not_active Ceased
- 1981-03-18 CA CA000373267A patent/CA1177823A/en not_active Expired
- 1981-03-18 NZ NZ196552A patent/NZ196552A/en unknown
- 1981-03-19 ZA ZA00811845A patent/ZA811845B/en unknown
- 1981-03-19 IL IL62433A patent/IL62433A0/en unknown
- 1981-03-20 JP JP3970581A patent/JPS56145291A/en active Pending
- 1981-03-20 EP EP81102128A patent/EP0036650A3/en not_active Withdrawn
- 1981-03-24 DK DK132981A patent/DK132981A/en not_active Application Discontinuation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5026843A (en) * | 1989-05-23 | 1991-06-25 | S.B.D. Synthetic And Biological Dvlpmnts. S.R.L. | Process for the preparation of ceftriaxone |
Also Published As
| Publication number | Publication date |
|---|---|
| AU6851281A (en) | 1981-10-01 |
| ZA811845B (en) | 1982-04-28 |
| NZ196552A (en) | 1984-07-06 |
| DK132981A (en) | 1981-09-26 |
| EP0036650A2 (en) | 1981-09-30 |
| AU536771B2 (en) | 1984-05-24 |
| JPS56145291A (en) | 1981-11-11 |
| IL62433A0 (en) | 1981-05-20 |
| EP0036650A3 (en) | 1982-11-10 |
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